Branched-chain amino acids as a novel biomarker and treatment for Alzheimer's disease

项目摘要 阿尔茨海默病(AD)是一种毁灭性的、不可逆转的神经退行性疾病，影响着500多万人 仅在美国就有个人。不幸的是，目前还没有治愈或有效治疗阿尔茨海默病的方法，而且缺乏 一系列准确评估个体易感性和预测AD未来发展的工具补充道 另一层复杂性。今天，医生们依靠几种生物标志物来诊断患有AD的人， 但目前的评估方法存在严重的局限性，如使用放射性同位素， 腰椎穿刺术风险大，费用高。显然，更可靠、更少侵入性和患者友好 人们迫切需要能够预测和/或诊断AD发病的生物标志物。我们的初步数据显示， 支链氨基酸(BCAA)及其代谢产物在阿尔茨海默病患者中升高 将转基因AD小鼠模型小鼠与健康对照组进行比较。与这些调查结果一致，BCAA是 在我们的预测模型中被确定为AD的重要综合预测因子(图1和图2)。此外，a 多项研究表明，过量的支链氨基酸可诱导神经氧化应激和细胞凋亡，触发胰岛素 大脑中的阻力，并抵消这些神经递质的平衡。有趣的是，所有这些都代表着 阿尔茨海默病的病理生理特征，提示支链氨基酸在阿尔茨海默病的发病机制中可能起作用 广告。我们的初步数据显示，在成熟的海马神经元中补充支链氨基酸可以诱导出 AD中常见的神经元功能障碍(图3)，使BCAA成为有吸引力的介入靶点 治疗AD。在拟议的研究中，实验将利用转基因、分子、综合生理学和 行为学方法检查1)支链氨基酸代谢在阿尔茨海默病样症状和 已建立的转基因小鼠模型(APP/PS1)的脑病理改变以确定血浆支链氨基酸和 它们的代谢产物可以作为AD的预测和/或诊断生物标志物；以及2)饮食中的支链氨基酸 在体内，操纵改变了AD的进展。这些发现将确定新的生物标记物用于预测和 AD的检测，并为支链氨基酸及其代谢在AD发生发展中的影响提供新的见解 广告。

Project Summary Alzheimer's disease (AD) is a devastating, irreversible neurodegenerative disorder that affects over 5 million individuals in the US alone. Unfortunately, currently there is no cure or effective treatment for AD, and the lack of tools to accurately assess an individual's susceptibility and predict one's future development of AD adds another layer of complexity. Today, doctors are relying on several biomarkers to diagnose individuals with AD, but there are serious limitations with current assessment methods such as the use of radioactive isotopes, high-risk lumbar puncture, and the high cost. Clearly, more reliable, less-invasive, and patient-friendly biomarkers that can predict and/or diagnose the onset of AD is highly desired. Our preliminary data show that branched-chain amino acids (BCAAs) and their metabolites are elevated in humans with AD as well as a transgenic mouse model of AD mice compared to healthy controls. In line with these findings, BCAAs are identified as a significant composite predictor of AD in our predictive model (Figs. 1 and 2). Furthermore, a number of studies suggest that excess BCAAs can induce neural oxidative stress and apoptosis, trigger insulin resistance in the brain, and offset the balance of those neurotransmitters. Interestingly, all of these represent the pathophysiological hallmarks of AD, indicating a potential causative role of BCAAs in the pathogenesis of AD. Our pilot data show that BCAA supplementation in mature hippocampal neurons induces features of neuronal dysfunctions commonly observed in AD (Fig. 3), making BCAAs an attractive interventional target to treat AD. Experiments in the proposed study will utilize transgenic, molecular, integrative physiology, and behavioral approaches to examine 1) BCAA metabolism before and after the onset of AD-like symptoms and brain pathologies in a well-established transgenic mouse model (APP/PS1) to determine if plasma BCAAs and their metabolites can serve as a predictive and/or diagnostic biomarker for AD; and 2) whether dietary BCAA manipulation alters the progression of AD in vivo. The findings will identify novel biomarkers for prediction and detection of AD and provide new insights into the impact of BCAAs and their metabolism in the development of AD.